Tidball Andrew M, Luo Jinghui, Walker J Clayton, Yang Charlotte Y, Lee Keithan, Spencer Ryan C, Matthews Carissa, Feng Geshan, Hsu Peggy P, Lee Yusoo, Morgan Jack, Childs Charlie J, Eiken Madeline K, Walton Katherine D, Spence Jason R
Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, USA; Michigan Neuroscience Institute, University of Michigan Medical School, Ann Arbor, MI, USA.
Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, USA.
Cell Rep. 2025 Jun 24;44(6):115842. doi: 10.1016/j.celrep.2025.115842. Epub 2025 Jun 10.
Apicobasal polarization is crucial for tissue organization during in vivo development and in human organoid models. Extracellular matrix (ECM) signaling typically provides a basal cue, and intestinal and lung organoids reverse polarity from apical-in to apical-out after ECM removal. However, ECM-free brain organoids maintain apical-in polarity, suggesting that media components may influence polarity. Exposing brain organoids to serum induced apical-out orientation. Lysophosphatidic acid (LPA), present in the medium of prior apical-out techniques, was identified as the causative factor. LPA-induced apical-out orientation in brain organoids occurred within 1 day, lasted at least 1 month, and was optimal at human cerebrospinal fluid LPA concentrations. Sphingosine-1-phosphate (S1P) induced similar apical-out polarization. Pharmacological studies revealed that LPA/S1P act via a G-protein coupled receptor/RhoA pathway. Finally, LPA induced apical-out polarity in patient-derived human lung and intestinal organoids, iPSC spheres, and multilineage iPSC-derived intestinal organoids. These findings indicate that LPA signaling is a critical apical polarity cue in multiple tissues.
顶基极化对于体内发育过程以及人类类器官模型中的组织构建至关重要。细胞外基质（ECM）信号通常提供一种基底信号，并且在去除ECM后，肠道和肺类器官会从顶向内极性转变为顶向外极性。然而，无ECM的脑类器官保持顶向内极性，这表明培养基成分可能会影响极性。将脑类器官暴露于血清中会诱导顶向外的方向。溶血磷脂酸（LPA）存在于先前顶向外技术的培养基中，被确定为致病因素。LPA诱导脑类器官顶向外方向的转变在1天内发生，持续至少1个月，并且在人脑脊液LPA浓度下最为理想。鞘氨醇-1-磷酸（S1P）诱导类似的顶向外极化。药理学研究表明，LPA/S1P通过G蛋白偶联受体/RhoA途径发挥作用。最后，LPA在患者来源的人类肺和肠道类器官、诱导多能干细胞（iPSC）球以及多谱系iPSC来源的肠道类器官中诱导顶向外极性。这些发现表明，LPA信号是多种组织中关键的顶极性信号。
